eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Wiskott-Aldrich Syndrome: Differential Diagnoses & Workup

Author: Robyn Siperstein, MD, Staff Physician, Department of Dermatology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School
Coauthor(s): Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Contributor Information and Disclosures

Updated: Feb 3, 2009

Differential Diagnoses

Agammaglobulinemia
Atopic Dermatitis
Bruton Agammaglobulinemia
DiGeorge Syndrome
Histiocytosis
Severe Combined Immunodeficiency

Other Problems to Be Considered

Physicians must distinguish between infants with bleeding and thrombocytopenia and infants with neonatal alloimmune thrombocytopenia. The presence of small platelets with mean platelet value (MPV) less than 6 fL characterizes Wiskott-Aldrich syndrome (WAS), whereas the other 2 disorders usually have large MPVs because of the young age of the platelets. However, the MPV is difficult to measure in the presence of profound thrombocytopenia (platelet count <10,000/dL).

X-linked thrombocytopenia is a mild phenotype of Wiskott-Aldrich syndrome with mutations in WASP that confer thrombocytopenia, possibly eczema, but no significant immunologic deficit. Sites for the WASP mutations in X-linked thrombocytopenia are somewhat different; thus, mutational analysis as well as clinical and laboratory data contribute to the final diagnosis of X-linked thrombocytopenia versus Wiskott-Aldrich syndrome (WAS). Differentiating this phenotype is important because stem cell reconstitution is not appropriate therapy for this clinically mild nonfatal disease.

The differential diagnosis of generalized eczema in infants includes Wiskott-Aldrich syndrome, as well as atopic dermatitis, seborrheic dermatitis, severe combined immunodeficiency (SCID), Langerhans cell histiocytosis, seborrheic dermatitis, Omenn syndrome, and ataxia-telangiectasia (AT).

AT presents with symptoms of eczema and recurrent infections; however, in contrast to Wiskott-Aldrich syndrome, patients with AT have decreased levels of immunoglobulin A (IgA) and, often, immunoglobulin E (IgE), and cerebellar ataxia is an early feature.

Wiskott-Aldrich syndrome is sometimes confused with Bruton agammaglobulinemia (X-linked agammaglobulinemia [XLA]) when the infant presents with recurrent otitis media, and when quantitative immunoglobulin levels show low immunoglobulin G (IgG). Patients with XLA are unlikely to have bleeding related to thrombocytopenia. Typically, Wiskott-Aldrich syndrome is associated with low immunoglobulin M (IgM) levels and normal-to-high immunoglobulin A (IgA) levels, whereas all immunoglobulin levels are undetectable in XLA. T-cell and B-cell population patterns are also characteristically different (normal CD19+ B cells and high CD4:CD8 ratios in Wiskott-Aldrich syndrome compared with absent CD19+ B cells and normal-to-elevated T cells in XLA).

X-linked hyperimmunoglobulin M (XHIM) syndrome may clinically resemble Wiskott-Aldrich syndrome, although bleeding manifestations are absent. Laboratory study findings should distinguish between them. Wiskott-Aldrich syndrome is associated with low IgM, high IgA, and high immunoglobulin E (IgE) levels; XHIM has normal-to-high IgM, low IgA, and low IgE levels. The pattern of T-cell abnormalities also differs as follows: high CD4:CD8 because of low CD8 in Wiskott-Aldrich syndrome compared with a normal ratio with lymphopenia in XHIM.

Other T-cell disorders occur early in infancy but without bleeding manifestations. Wiskott-Aldrich syndrome and other T-cell disorders share an increased incidence of dermatitis. X-linked severe combined immunodeficiency (X-SCID) is usually clinically different because of the early presence of more significant opportunistic and viral infections. Fluorocytometric analysis of T-cell and B-cell populations is used to distinguish Wiskott-Aldrich syndrome from X-SCID and other forms of SCID, such as major histocompatibility (MHC) class II deficiency ("bare lymphocyte" syndrome).

See Table 1 in Severe Combined Immunodeficiency.

Workup

Laboratory Studies

  • CBC counts often support the diagnosis of Wiskott-Aldrich syndrome (WAS). MPV is a routine component of the automated CBC count. Platelets are less than 70,000/mL. The mean platelet volume (MPV) is less than 5 fL.
  • Always interpret quantitative immunoglobulin levels based on age-related reference range values. Classic Wiskott-Aldrich syndrome is associated with low immunoglobulin M (IgM) and immunoglobulin G (IgG) levels, with normal-to-high immunoglobulin A (IgA) and immunoglobulin E (IgE) levels. However, young infants in particular may not show classic immunoglobulin abnormalities because Wiskott-Aldrich syndrome is associated with attrition in immunologic functions.
  • Specific antibody defects are most likely in response to polysaccharide antigens. Therefore, isohemagglutinins, IgM directed against the ABO blood group antigens, are typically absent; isohemagglutinins are age-related and are not detectable until infants are older than approximately 6 months. IgG directed against unconjugated pneumococcal antigens are determined postvaccination but are not produced by healthy children younger than 2 years. T-dependent antibody responses to tetanus, diphtheria, and conjugated Hib vaccines vary in Wiskott-Aldrich syndrome. Immune attrition in antibody responses occurs in older patients.
  • Classic Wiskott-Aldrich syndrome is associated with anergy to delayed-type hypersensitivity (DTH) skin tests. Conventional antigens for DTH testing are tetanus, diphtheria, and Candida; however, immunocompetent infants must have been exposed to the antigen 4-6 weeks prior to testing in order for a positive response to be present. In vitro tests for T-cell function show normal responses in young patients with Wiskott-Aldrich syndrome using nonspecific mitogens such as phytohemagglutinin, concanavalin A, and pokeweed as the stimulus. Defects in T-cell responses are more consistent using allogeneic lymphocytes or periodate as the stimulus. As with humoral responses, Wiskott-Aldrich syndrome is associated with immune attrition of cell-mediated immunity over time.
  • Autoantibodies may be detected in autoimmune hemolytic anemia (AIHA), immune neutropenia, or immune thrombocytopenia. Such antibodies are the same as those observed in immunocompetent patients.
  • When a T-cell disorder is suspected, the Immune Deficiency Foundation has a consultative service for physicians. Laboratories in Seattle (the University of Washington), Boston (Children's Hospital), and New York City are funded to provide molecular analysis (Jeffrey Modell Foundation), or they can assist in contacting other research facilities.

Imaging Studies

  • Radiography, particularly of the chest, is part of the assessment for new infections.
  • CT and MRI studies are usually not part of Wiskott-Aldrich syndrome management unless stem cell reconstitution procedures have been performed and posttransplantation complications have developed.

Other Tests

  • Appropriate cultures and sensitivities are essential to manage acute infections. Blood cultures are especially important in splenectomized patients with Wiskott-Aldrich syndrome, but any patient has increased risk for bacteremia with polysaccharide-coated bacteria.
  • Monitor renal function and hepatic function at regular intervals.
  • Workup to determine feasibility for stem cell transplantation requires major histocompatibility (MHC) tests of the patient, parents, and siblings. Screen both the patient and potential donor for infectious agents, including human immunodeficiency virus (HIV), cytomegalovirus (CMV), and hepatitis viruses. Pulmonary, hepatic, and neurologic evaluations of the patient are required to assess chronic organ dysfunction.
  • Blinded food trials are the criterion standard for determination of food hypersensitivity. However, no adequately studied reports exist of the incidence of food sensitivity or the effect of food restriction on the eczematous dermatitis of Wiskott-Aldrich syndrome. The radioallergosorbent assay test (RAST) for food sensitivity is insensitive, and findings often do not correlate with clinical symptoms.

Procedures

  • No procedures are routinely performed.

Histologic Findings

  • Older patients with Wiskott-Aldrich syndrome have involution of lymphoid tissues, but depletion of lymphocytes is subtle in younger patients who show only poor development of the follicular areas.
  • Lymphoid tissues of the gut usually are relatively normal.
  • The thymus may be small but shows normal architecture, including Hassall corpuscles.
  • T cells are remarkable for the lack of surface microvilli on which CD43 are expressed in normal lymphocytes.
  • Specialized techniques can be used to detect poor filopodia formation in platelets and poor F-actin capping at phagocytic vacuoles in phagocytes.

More on Wiskott-Aldrich Syndrome

Overview: Wiskott-Aldrich Syndrome
Differential Diagnoses & Workup: Wiskott-Aldrich Syndrome
Treatment & Medication: Wiskott-Aldrich Syndrome
Follow-up: Wiskott-Aldrich Syndrome
Multimedia: Wiskott-Aldrich Syndrome
References
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Further Reading

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Keywords

Wiskott-Aldrich syndrome, WAS, Wiskott-Aldrich-Huntley syndrome, eczema-thrombocytopenia syndrome, eczema-thrombocytopenia-diarrhea syndrome, eczema-thrombocytopenia immunodeficiency syndrome, X-linked thrombocytopenia, intermittent thrombocytopenia, neutropenia, lymphomas, leukemia, atopic dermatitis, otitis media, pneumonia, sepsis, meningitis, reactive airway disease, allergic rhinitis, Haemophilus influenzae type B, Hib, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, varicella-zoster virus, herpes simplex virus, autoimmune hemolytic anemia, AIHA, arthritis, nephritis, immune thrombocytopenia, non-Hodgkin lymphoma, impetigo, cellulitis, furuncles, abscesses, eczema herpeticum, molluscum, sinonasal infections, pharyngitis, thrush

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Contributor Information and Disclosures

Author

Robyn Siperstein, MD, Staff Physician, Department of Dermatology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School
Robyn Siperstein, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Society for MOHS Surgery, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

James M Oleske, MD, MPH, François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, New Jersey Medical School
James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

David J Valacer, MD, Consulting Staff, Hoffman La Roche Pharmaceuticals
David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

CME Editor

David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville
David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology
Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School
Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

 
 
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